Benign synthesis of terpene-based 1,4-p-menthane diamine

Terpenes represent a promising renewable feedstock for the substitution of fossil resources in the synthesis of renewable platform chemicals, like diamines. This work describes the synthesis and full characterization of 1,4-p-menthane diamine (1,4-PMD) obtained from α-terpinene (1). A two-step procedure using dibenzyl azodicarboxylate (DBAD) and H2 as rather benign reagents was employed under comparatively mild conditions. Both C–N bonds were formed simultaneously during a visible-light mediated Diels–Alder reaction, which was investigated in batch or flow, avoiding regioselectivity issues during the amination steps that are otherwise typical for terpene chemistry. Heterogeneously catalyzed quadruple hydrogenation of the cycloadduct (2a) yielded 1,4‑PMD (3). While the intermediate cycloadduct was shown to be distillable, the target diamine can be sublimed, offering sustainable purification methods.


Used compounds
If not stated otherwise, all used compounds were purchased from chemical suppliers and used without further purification.The key starting material of this work, α-terpinene (1), was purchased from Alfa Aesar and the purity was determined by GC and NMR experiments to be 73%.The compound was used without further purification, but the used masses and volumes given in the synthetic procedure correspond the actual included amount of 1.

Flash column chromatography
The purification of compounds by flash column chromatography proceeded referring to the idea of W. C. Still et al. [2] As stationary phase, silica of technical grade with 60 Å pore size, 230 -400 mesh size and 40 -63 µm particle size from Sigma Aldrich was used.The eluent is given for each compound separately in section 3.As apparatus, glass columns with integrated frits of different pore sizes and valves were used.Applied pressures for faster flows were achieved by manual pumps.

Reactions applying H2 pressure
Hydrogenations under high pressures were conducted in a 300 mL Berghof pressure reactor with Teflon inlet.Via an integrated thermometer, the temperature was monitored during the reaction.The pressure reactor was placed on a magnet stirrer, to enable stirring of the reaction mixture.

Reaction under UV irradiation
All reactions under UV irradiation were conducted using one of two LED-arrays with the same principal setup, but different sizes.Both setups consist of a magnetic stirrer, an aluminum cooling element with LEDs attached to it and a vial block with six (Figure S1

Preparation and use of Raney-Ni
Within this work, the term "freshly prepared Raney-Nickel" refers to elementary Nickel, which was obtained by leaching of a nickel/aluminum alloy (1:1 weight proportion) and was not stored longer than for two weeks.
For the preparation of freshly prepared Raney-Nickel, 20.3 g Ni/Al alloy were carefully added portion wise to 220 mL of 3.64 mol/L NaOH(aq) at 80 °C under vigorous stirring.This proceeded slowly, due to strong exothermic gas development (H2 ↑).After the alloy was added completely to the NaOH solution, the mixture was further stirred at 80 °C until no gas development was observed anymore (~20 minutes) to ensure full oxidation and dissolution of aluminum.The aqueous suspension was cooled to room temperature, decanted, and the resulting solid was washed three times with deionized water and three times with ethanol (HPLC grade) subsequently.After the last washing step, the obtained black nickel was suspended in 87.3 mL ethanol, yielding a nickel/ethanol slurry with a concentration of 0.116 g/mL.
The nickel/ethanol slurry was shaken vigorously before it was added to reaction mixtures, to warrant homogeneity and constant concentration of the slurry.The slurry was stored in a polyethylene screw-cap container, which was sealed additionally with parafilm, to avoid evaporation of the solvent, thus alterations of concentration.

Thin layer chromatography
TLC measurements were conducted on silica gel coated aluminum plates of type F254, supplied by Sigma Aldrich.After spotting of the compounds on the TLC plates, the plates were placed in a glass chamber filled with a filling level of 0.5 cm of eluent.After one iteration of eluent flow, the compounds spots were visualized by UV light (254 or 365 nm), by KMnO4 solution or by Seebach stain.For determination of the Rf-values of unreported compounds, 1 mg of the isolated substance was dissolved in 1 mL of CH2Cl2 and spotted slightly.

Fourier transformation infrared spectroscopy (FT-IR)
FT-IR measurements were conducted using a Bruker Alpha FTIR spectrometer with Platinum technology.Each measurement consisted of one background measurement and one transmission measurement with 24 scans.The IR-spectra show the bands of the investigated compounds as transmittance from 0-1 relative to the wavenumber in cm⁻ 1 from 4,000 to 400 cm ⁻1 , due to convention.

High resolution mass spectrometry
HRMS measurements were conducted on a Finnigan MAT 95 spectrometer using fast atom bombardment ionization (FAB).

Atmospheric solids analysis probe mass spectrometry (ASAP-MS)
ASAP-MS measurements were conducted using an Advion expression CMS system.

Single-crystal X-ray diffractometry (SC-XRD)
Diffraction data were measured using a Stoe IPDS II diffractometer and graphitemonochromated MoKα (0.71073 Å) radiation.Absorption corrections were carried out using the STOE LANA software package. [4]Structure solution were carried out using OLEX2 1.5 [5] by dual-space direct methods with SHELXT, [6] by full-matrix least-squares refinement using SHELXL-2014/7. [7]All non-hydrogen atoms were refined anisotropically.The contribution of the hydrogen atoms, in their calculated positions, was included in the refinement using a riding model.A full listing of atomic coordinates, bond lengths, angles and displacement parameters for all the structures have been deposited at the Cambridge Crystallographic Data Centre.For the individual numbers, please refer to the XRD table in section 6.

UV/VIS measurements of dibenzyl azodicarboxylate
Absorption spectra were recorded using a CARY 3500 UV/VIS spectrometer by Agilent.

Figure S3
. Absorption spectrum of DBAD in acetone.
Anisole was added for standardization and the mixtures were investigated by NMR spectroscopy.
In the case of DMSO, the reaction and 1 H NMR measurements were both directly conducted in DMSO-d6.
Table S3. 1 H NMR yields of solvent screening of photochemical reaction between 1 and DBAD.

Figure S2 .
Figure S2.Flow reactor by Vapourtec used in this work.